The candidate's goal is to become an independent investigator in the field of genetic epidemiology, specifically studying environmental and genetic risk factors that interact to cause congenital heart disease. She will acquire new skills in genetic epidemiology and statistical genetics and will use the methodological and statistical training acquired from this K08 award to perform sophisticated gene-environmental studies using epidemiological data and biological samples from the National Birth Defects Prevention Study. She will perform research under the guidance of a genetic epidemiologist and statistical geneticist with expertise in the field of cardiovascular genetic epidemiology. The candidate will be in a Pediatric Department that has afforded her protected research time and access to state-of-the-art facilities. The long term objectives of the project are to investigate underlying genetic susceptibilities in the complex etiology of congenital heart defects (CHDs). These are the most prevalent and serious of all recognized birth defects, occurring in 8 to 10 of every 1,000 live births in the US. During initial work, it was found that a maternal history of smoking during pregnancy significantly increased the risk of atrial and ventricular septal heart defects which combined account for almost 50% of all CHD in infants. This study hypothesis is that specific genetic polymorphisms that encode DMA repair enzymes increase the risk of septal heart defects among offspring prenatally exposed to tobacco. The candidate will use new genomic tools provided by the Human Genome Project and the International HapMap Project as well as access to the largest case-control study of birth defects ever conducted in the US, the National Birth Defect Prevention Study to test this hypothesis. If this hypothesis is confirmed, the resulting genetic profiles can be used in future projects to establish a program to prevent and eventually reduce the prevalence of CHDs. The specific aims of this project are: Specific Aim 1: Identify a set of highly informative, haplotype-tagging, single nucleotide polymorphisms (htSNPs) within selected DNA repair genes using data generated from Phase I and Phase II of the International HapMap Project Specific Aim 2: Determine if selected htSNPs are associated with septal heart defects by conducting a case control and case-parental association study. This project is designed to identify a panel of risk genes that are associated with septal heart defects. Identification of the molecular basis of septal heart defects will enable better diagnostic tools to be developed to identify mothers at risk. Our long-term goal is to combine an accurate history of exposure to tobacco with analysis of specific risk genes in the mother to create a risk profile for identifying mothers at risk of having children with CHDs. (End of Abstract)